Brain or spinal cord injury is associated with significant morbidity and mortality and can occur as a result of, for example, intracerebral hemorrhage (ICH), stroke, traumatic brain injury, brain tumors, arterio-venous malformations, amyloid angiopathy, anticoagulant use, or sickle cell disease. Brain injury resulting from ICH is particularly prevalent, with a worldwide incidence of 10-20 cases per 100,000 people. As therapies targeted at reducing primary injury have been largely unsuccessful, there has been a renewed focus on secondary injury mechanisms. In particular, blood breakdown products in the brain after ICH appear to be an important source of secondary injury. Specifically, functional impairment is associated with red blood cell lysis, release of heme, and increases in redox active iron. In this scheme, free iron is able to interact with peroxide to generate highly reactive hydroxyl radicals via Fenton Chemistry and oxidative damage to lipid, protein and DNA in diverse cell types.
A class of metalloenzymes that has been implicated in neuronal survival in vitro and in vivo is a family of oxygen sensors known as the hypoxia inducible factor prolyl hydroxylase domain enzymes (HIF PHDs). These oxygen, 2-oxoglutarate, and iron-dependent dioxygenases destabilize the transcriptional activator, HIF-1α under normoxia. Iron chelators are known to inhibit the HIF prolyl hydroxylases in normoxia, thus inhibiting oxygen-dependent hydroxylation of HIF, its recruitment of VHL, and its proteosomal degradation. Iron chelators have also been shown to stabilize HIF-1 and activate a suite of putative adaptive genes at concentrations where they protect neurons from oxidative death.
Although chelation of iron has its benefits, there would be a greater benefit in preventing hemin-induced neuronal death by targeting HIF PHDs rather than free iron. Nevertheless, until now, such a methodology has remained elusive.